A three-run fifth-inning from the Dodgers, after both starting pitchers dominated early, blew the game open as the Cubs offense struggled to gain momentum, getting just three hits in nine innings.
Ohtani, last season's MVP and an icon in Japan, was the headline attraction for the fans in the Tokyo Dome, but a ground-out to second base was an anti-climax to the season opener.
LA would have to rely on Ohtani on opening night as both Mookie Betts and Freddie Freeman were ruled out prior to the game and it was a slow start as both sides struggled for hits in the early going.
Another Japanese star, Seiya Suzuki, broke his bat early facing Los Angeles' Yoshinobu Yamamoto in a sign that it could be a pitcher's duel in the Japanese capital.
However, a double from Chicago catcher Miguel Amaya into the gap brought home the first run of the game in the third inning as Dansby Swanson scored from second base.
The first half of the game belonged to Chicago and starting pitcher Shota Imanaga who threw four shutout innings (2K, 0H 4BB) before being replaced by Ben Brown at the top of the fifth inning. Unsurprising given the shortened spring training for both sides.
That change was taken advantage of by the Dodgers. First, Andy Pages got on base before Ohtani got his first hit of the night.
After a strikeout for Brown and a single from Tommy Edman, Teoscar Hernandez hit a stinging shot to right field that couldn't be pouched by Ian Happ, allowing LA to tie the game at 1-1 with Pages coming home to score.
A botched double play from the Cubs gave LA the lead as the ball was thrown away and Will Smith added to a poor fifth inning for Chicago, hitting a single into left that brought Hernandez round third and home for a 3-1 lead. Brown would get out of the inning with a punch-out against Max Muncy, but the damage was already done.
The game headed into the ninth with the Cubs down by two and with Ohtani leading off for the Dodgers, he notched up his second hit of the night to end the day 2-5 with a double. He was moved over to third for the first out, before Hernandez smoked an RBI single to extend the lead.
Tanner Scott came in at the bottom of the ninth for Los Angeles, getting three quick outs to deliver a 4-1 victory in what was a dominant pitching performance from the Dodgers.
The two teams go at it again on Wednesday with the final game of the Tokyo Series, where Roki Sasaki will make his big league debut with the Dodgers after signing from Japan in the off-season.
The MLB season for the other 28 teams gets going next Thursday for the traditional opening day.